Triazole derivative or salt thereof, preparation process thereof and pharmaceutical containing said compound as an effective ingredient

ABSTRACT

Described is a triazole derivative represented by the formula (1):                    
     wherein R 1  represents a hydrogen atom, a lower alkyl group or an aralkyl group, X 1  and X 2  are the same or different and each independently represents a hydrogen atom, a halogen atom or a halogenoalkyl and n stands for an integer of 0 to 2, or salt thereof; a preparation process of said compound and a pharmaceutical comprising said compound as an effective ingredient. 
     The compound as described above has high antimycotic activity and is useful for the prevention and treatment of mammalian mycotic infections.

This application is a Division of application Ser. No. 09/471,286 Filedon Dec. 23, 1999, which is pending; and U.S. Ser. No. 09/235,320 filedJan. 22, 1999, now U.S. Pat. No. 6,040,325.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to a triazole derivative or salt thereof whichhas excellent antimycotic action and high safety, an intermediate forpreparing said compound and a pharmaceutical comprising said compound asan effective ingredient.

2. Description of the Related Art

Mycosis can be classified into two types, that is, superficial mycosisrepresented by various trichophytosis, marginated eczema, psoriasis,cutaneous candidiasis or the like and deep seated mycosis represented bymycotic meningitis, mycotic infectious disease of respiratory organ,fungemia, mycosis of urinary tract or the like. Of these, deep seatedmycosis such as candidiasis or aspergillosis tends to show a markedincrease in recent days owing to the frequent use of an anticancerchemotherapeutic agent or immunosuppressive agent or lowering in thebioimmunology due to HIV infection or the like. There is accordingly ademand for a pharmaceutical efficacious against fungi causing suchdiseases.

As pharmaceuticals effective against Aspergillus spp. and Candida spp.,Amphotericin B and azole base compounds such as Fluconazole andItraconazole are conventionally known, but not so many pharmaceuticalshave been commercially available yet. In addition, the above-exemplifiedpharmaceuticals involve problems in safety and antimycotic action. Thereis accordingly a demand for an antimycotic effective against Aspergillusspp. and Candida spp. Now, more effective azole base compounds are underdevelopment. For example, as a compound having a difluoromethylenegroup, those described in Japanese Patent Application Laid-Open Nos.163374/1984, 163269/1993 and 227531/1997 are known. As an azole basecompound having a substituted tertiary hydroxyl group, cyclic compoundsas described in Japanese Patent Application Laid-Open Nos. 217778/1996and 333367/1996, acyl compounds as described in Japanese PatentApplication Laid-Open Nos. 104676/1996 and 183769/1997, and the like areknown but they are not fully satisfactory.

SUMMARY OF THE INVENTION

Accordingly, an object of the present invention is to provide a compoundwhich has high safety and has antimycotic activity effective againstAspergillus spp. and Candida spp.

With the forgoing in view, the present inventors synthesized a number oftriazole derivatives and salts thereof and carried out an investigationon their antimycotic activity effective against Aspergillus spp. andCandida spp. As a result, it has been found that a cyclopropylthio- orcyclopropylsulfonyl-containing triazole derivative represented by thebelow-described formula (1) and a salt thereof are superior inantimycotic activity against fungi including Aspergillus spp. andCandida spp. and also in safety to the analogous compounds which havebeen known to date, leading to the completion of the present invention.In one aspect of the present invention, there are thus provided atriazole derivative represented by the following formula (1):

wherein R¹ represents a hydrogen atom, lower alkyl group or aralkylgroup, X¹ and X² are the same or different and each independentlyrepresents a hydrogen atom, a halogen atom or a halogenoalkyl group andn stands for an integer of 0 to 2, or salt thereof; an intermediate forpreparing said compound; and a preparation process of these compounds.

In another aspect of the present invention, there is also provided apharmaceutical comprising as an effective ingredient the triazolederivative represented by the formula (1) or salt thereof.

In a further aspect of the present invention, there is also provided apharmaceutical composition comprising the triazole derivativerepresented by the formula (1) or salt thereof and a pharmacologicallyacceptable carrier.

In a still further aspect of the present invention, there is alsoprovided the use of the triazole derivative represented by the formula(1) or salt thereof as a pharmaceutical.

In a still further aspect of the present invention, there is alsoprovided a treating method of mycotic infections, which comprisesadministering to a patient a pharmacologically effective amount of thetriazole derivative represented by the formula (1) or salt thereof.

The triazole derivative or salt thereof according to the presentinvention has strong antimycotic activity, and an antimycotic comprisingsuch compound as an effective ingredient is useful for the preventionand treatment of mycotic infections of mammary animals including humans.

BRIEF DESCRIPTION OF THE PREFERRED EMBODIMENTS

In the triazole derivative of the present invention, examples of thelower alkyl group represented by R¹ in the formula (1) include linear orbranched C₁₋₆ alkyl groups. Specific examples include methyl, ethyl,n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl,i-pentyl and n-hexyl. As the aralkyl group represented by R¹, C₇₋₁₀aralkyl groups are preferred, with phenyl-C₁₋₄ alkyl groups being morepreferred. Specific examples include benzyl, phenethyl and phenylpropyl.As R¹, methyl and benzyl groups are preferred. In X¹ or X², examples ofthe halogen atom include fluorine, chlorine, bromine and iodine atoms,with the fluorine and chlorine atoms being particularly preferred.Examples of the halogenoalkyl group include the above-exemplified C₁₋₆alkyl groups each substituted by the above-exemplified halogen atom.Among them, perfluoro-C₁₋₆ alkyl groups are preferred, withtrifluoromethyl and pentafluoroethyl groups being particularly preferredand trifluoromethyl group being more preferred. The number n of oxygenatoms stands for an integer of 0 to 2, with 0 or 2 being preferred.

No particular limitation is imposed on the salt of the triazolederivative (1) of the present invention insofar as it is apharmacologically acceptable salt. Examples include acid addition saltssuch as hydrochlorides, nitrates, hydrobromides, p-toluenesulfonates,methanesulfonates, fumarates, succinates and lactates.

The triazole derivative (1) or salt thereof according to the presentinvention has stereoisomers based on its asymmetric carbon andsulfoxide. The present invention embraces any one of such isomers andisomer mixtures such as racemic modifications. The triazole derivative(1) or salt thereof may exist in the form of a solvate typified by ahydrate. The present invention also embraces solvates of thesecompounds.

The triazole derivative (1) of the present invention can be prepared,for example, in accordance with the reaction scheme described below:

wherein R¹, X¹ and X² have the same meanings as defined above and X³represents a halogen atom.

Described specifically, Compound (1a), that is, a compound of theformula (1) wherein n stands for 0 can be prepared by introducing acyclopropylthio group into a 2-haloacetophenone derivative (5) which isa known compound; difluorinating the resulting cyclopropylthio compound(4) into Compound (2); and directly introducing a triazolemethyl groupinto Compound (2) or first introducing an epoxymethylene group intoCompound (2) to obtain Compound (3) and then introducing a triazolegroup into Compound (3). The R¹ of the resulting Compound (1a) can bealkylated or aralkylated as desired. By the oxidation of Compound (1a),Compound (1b), that is, a compound of the formula (1) wherein n standsfor 1 or Compound (1c), that is, a compound of the formula (1) wherein nstands for 2 can be prepared. Alternatively, Compound (1c) can beprepared by the oxidation of Compound (1b).

In the above preparation process, the2,2-difluoro-2-cyclopropylthioacetophenone derivative represented by theformula (2) and oxirane derivative represented by the. formula (3) arenovel compounds synthesized by the present inventors and are useful asan intermediate for the synthesis of a triazole derivative (1).

The present invention will hereinafter be described in accordance withthe above steps.

Step (5-4):

Compound (4) can be prepared by introducing a cyclopropylthio group intoCompound (5).

In Compound (5) employed as a starting material, examples of X³ in theformula (5) include fluorine, chlorine and bromine atoms. Among them,chlorine and bromine atoms are preferred. Compound (5) which contains asX³ a fluorine, chlorine or bromine atom and as X¹ and X² a fluorine atomare commercially available, for example, from Aldrich Chemical Co., Inc.

Compound (4) can be prepared by reacting Compound (5) with acyclopropylthio-introducing agent in the presence of a base. As thecyclopropylthio-introducing agent, cyclopropylmercaptane [J. Am. Chem.Soc., 114, 3492(1992)] is preferred. Examples of the reaction solventinclude methanol, ethanol, diethyl ether, a methanol-diethyl ethersolvent mixture, N,N-dimethylformamide, 1,4-dioxane and tetrahydrofuran,with methanol and methanol-diethyl ether solvent mixture beingparticularly preferred. As the base, any one of sodium carbonate,potassium carbonate, sodium hydroxide, potassium hydroxide, bariumhydroxide, sodium hydride, potassium hydride, sodium methoxide, sodiumethoxide, pyridine, triethylamine and the like is usable, with potassiumcarbonate being preferred.

Step (4-2)

Compound (2) can be prepared by reacting Compound (4) with afluorinating reagent in a solvent.

Examples of the fluorinating agent include fluorine gas, perchlorylfluoride, potassium fluoride, spray-dried potassium fluoride,freeze-dried potassium fluoride, tetraalkylammonium fluoride,tris(dimethylamino)-sulfa(trimethylsilyl)difluoride, N-fluoropyridone,N-fluoro-N-alkyl-arenesulfonamide, N-fluoroquinuclidinium salt,N-fluoroperfluoroalkyl sulfonimide, N-fluorosaltum, fluorinated xenon,N-fluoropyridinium salt and N-fluoropyridinium sulfonate. Examples ofthe commercially available fluorinating reagent include “OnodaFluorinates FP-T300, FP-T500, FP-T700, FP-B300, FP-B500, FP-B700 andFP-B800” (trade names; products of Chichibu Onoda Co., Ltd.) and“MEC-01, MEC-02, MEC-03, MEC-04 and MEC-05” (trade names; products ofDaikin Industries, Ltd.). It is preferred to use the fluorinatingreagent in an amount of 2 to 20 equivalents per mole of Compound (4).Illustrative of the reaction solvent include 1,2-dichloroethane,1,1,2-trichloroethane, chloroform, methylene chloride, diethyl ether,ethyl acetate and tetrahydrofuran. Among them, 1,1,2-trichloroethane ispreferred. The reaction temperature is −78° C. to the boiling point ofthe solvent, with 80 to 100° C. being preferred.

To improve the yield of the compound, a Lewis acid or a base can beused. Exemplary Lewis acids include aluminum chloride, zinc chloride andstannic chloride, while exemplary bases include sodium hydroxide,potassium hydroxide, barium hydroxide, sodium carbonate, potassiumcarbonate, sodium hydride, potassium tert-butoxide, lithiumdiisopropylamide and potassium hexamethyldisilazane.

Step (2-1a):

Direct synthesis from Compound (2) to Compound (1a) is carried out byreacting 1 mole of Compound (2) with 1 to 5 moles of an epoxymethylatingagent and 1 to 4 moles of 1,2,4-triazole or alkaline metal salt thereofat −100° C. to room temperature or boiling point of the solvent for 1 to30 hours in a solvent. Examples of the epoxymethylating agent includetrimethylsulfoxonium iodide and trimethylsulfonium iodide. Examples ofthe base include sodium hydroxide, potassium hydroxide, bariumhydroxide, sodium methoxide, sodium carbonate, potassium carbonate andsodium hydride, with potassium hydroxide being particularly preferred.As the solvent, methanol, ethanol, isopropanol, n-butanol, sec-butanol,t-butanol and the like are preferred.

Step (2-3)

Compound (1a) can be prepared via Compound (3).

Compound (3) can be obtained by reacting, in a solvent, Compound (2)with 1 to 2 equivalents of an epoxymethylating agent such astrimethylsulfoxonium iodide or trimethylsulfonium iodide in the presenceof 1 to 5 equivalents of an alkali. Dimethylsulfoxide, tetrahydrofuranor the like can be suitably used as a solvent. Examples of the baseinclude sodium hydroxide, potassium hydroxide, barium hydroxide, sodiummethoxide, sodium ethoxide, sodium carbonate, potassium carbonate andsodium hydride, with sodium hydride being particularly preferred. Thereaction temperature preferably ranges from −100° C. to the boilingpoint of the solvent, with a range of from −40 to 50° C. beingparticularly preferred.

Step (3-1a):

Compound (1a) can be prepared by reacting Compound (3) with1,2,4-triazole or alkali metal salt thereof in a solvent in the presenceof a base. Preferred examples of the solvent includeN,N-dimethylformamide, acetonitrile, N,N-dimethlacetamide anddimethylsulfoxide. Examples of the base include sodium hydroxide,potassium hydroxide, barium hydroxide, sodium carbonate, potassiumcarbonate and tert-butoxy potassium. The reaction temperature preferablyranges from 0° C. to the boiling point of the solvent, with a range of20 to 60° C. being particularly preferred.

The tertiary hydroxyl group of Compound (1a) can be alkylated as neededin the presence of a base. Examples of the alkyl halide to be used forthe alkylation include methyl iodide, ethyl iodide, propyl iodide andbenzyl chloride. Examples of the base include sodium hydroxide,potassium hydroxide, barium hydroxide, sodium carbonate, potassiumcarbonate and sodium hydride. Examples of the solvent include alcoholicsolvents such as methanol and ethanol, nonaqueous polar solvents such asN,N-dimethylformamide and ether solvents such as 1,4-dioxane andtetrahydrofuran, with N,N-dimethylformamide being particularlypreferred. The reaction temperature preferably ranges from −40° C. tothe boiling point of the solvent, with 0 to 20° C. being particularlypreferred.

Step (1a-1c):

Compound (1c) can be prepared by adding at least 2 equivalents,preferably 2.2 to 2.3 equivalents of an oxidizing agent to Compound(1a). Examples of the oxidizing agent include m-chloroperbenzoic acid,aqueous hydrogen peroxide, peracetic acid, tetrapropylammoniumperruthenate, osmium tetraoxide, potassium permanganate and oxone.Illustrative of the solvent include chloroform, dichloromethane, aceticacid, methanol, water, acetonitrile and carbon tetrachloride, andmixtures thereof. The reaction temperature preferably ranges from −40°C. to the boiling point of the solvent, with 0 to 50° C. beingparticularly preferred. To improve the yield, ruthenium trichloride,selenium dioxide, sodium tungstate, sodium molybdate and vanadium oxidemay be used as a catalyst.

Step (1a-1b) and Step (1b-1c):

Compound (1b) can be prepared by adding 1 to 2 equivalents, preferably1.2 equivalents of an oxidizing agent to Compound (1a). Examples of theoxidizing agent include m-chloroperbenzoic acid, aqueous hydrogenperoxide, peracetic acid, tetrapropylammonium perruthenate, osmiumtetraoxide, potassium permanganate and oxone. Illustrative of thesolvent include chloroform, dichloromethane, acetic acid, methanol,water, acetonitrile and carbon tetrachloride, and mixtures thereof. Thereaction temperature preferably ranges from −40° C. to the boiling pointof the solvent, with 0 to 50° C. being particularly preferred. Toimprove the yield, ruthenium trichloride, selenium dioxide, sodiumtungstate, sodium molybdate and vanadium oxide may be used as acatalyst. Step (1b-1c) can be carried out similarly.

Compounds (1a), (1b) and (1c) each has enantiomers based on itsasymmetric carbon atom. Such an optically active substance can beprepared by separating using a column for separation of an opticalisomer. Examples of the optically active stationary phase includesynthetic optically active polymers, natural high molecules and aminoacid metal complexes. Among them, a cellulose-derivative-coated silicagel is preferred. As a column filled with thiscellulose-derivative-coated silica gel, commercially-available productssuch as CHIRALCEL OD and CHIRALPAK AS (each, trade name; product ofDaicel Chemical Industries, Ltd.) can be used, with CHIRALCEL OD beingparticularly preferred. As chromatography, liquid chromatography ispreferred. In this case, hexane—ethanol, hexane—isopropyl alcohol, orthe like can be used as an eluent as a mobile phase. The opticallyactive substance can also be prepared by optical resolution. Examples ofthe reagent for optical resolution include optically activecamphor-sulfonic acid or salt thereof which may be substituted with ahalogen atom. Specific examples include (+)-camphor-10-sulfonic acid,(−)-camphor-10-sulfonic acid, (+)-3-bromocamphor-8-sulfonic acid,(−)-3-bromocamphor-8-sulfonic acid, (+)-3-bromocamphor-10-sulfonic acid,(−)-3-bromocamphor-10-sulfonic acid, ammonium(+)-3-bromocamphor-8-sulfonate and ammonium(−)-3-bromocamphor-8-sulfonate. Among them,(+)-3-bromocamphor-8-sulfonic acid, (−)-3-bromocamphor-8-sulfonic acid,ammonium (+)-3-bromocamphor-8-sulfonate and ammonium(−)-3-bromocamphor-8-sulfonate are particularly preferred.

No particular limitation is imposed on the isolation means of a targetproduct from the reaction mixture available by each of theabove-described reactions. The target product can be isolated, forexample, by recrystallization, various types of chromatography or thelike. Moreover, the target compound can be converted into a desired saltin a conventional manner.

The compound (1) of the present invention or salt thereof exhibitsexcellent antimycotic action against fungi including Aspergillus spp.and Candida spp. in vitro and in vivo and has high safety so that it isuseful as a pharmaceutical for the prevention and treatment of mycoticinfections.

From the invention compound (1), a pharmaceutical, particularly, anantimycotic can be obtained in various dosage forms such as tablets,granules, powders, capsules, suspensions, injections, suppositories andexternal preparations in a conventional manner. Such a pharmaceuticalcomposition can be prepared by incorporating a pharmacologicallyacceptable carrier in Compound (1). Described specifically, a solidpreparation can be prepared in a conventional manner by adding to theinvention compound (1) an excipient and, if necessary, a binder,disintegrator, extender, coating agent, sugar-coating agent and/or thelike. An injection may be prepared by dissolving, dispersing oremulsifying the invention compound (1) in an aqueous carrier such asdistilled water for injection to form an injection liquid in advance orto prepare powder for injection and dissolve it upon use. Examples ofthe administration method of the injection include intravenousadministration, intraarterial administration, subcutaneousadministration and instillation.

The dose of the invention compound (1) or salt thereof as apharmaceutical differs depending on various factors such as the kind ofthe disease; symptoms, weight, age or sex of the patient to beadministered; or administration route. When used as an antimycotic, thepharmaceutical is used in an amount of 0.1 to 1000 mg/day, preferably 1to 300 mg/day per adult in terms of the invention compound (1) or saltthereof. It is possible to add the above-described amount once a day or2 to 4 portions a day.

EXAMPLES

The present invention will hereinafter be described in detail byreferential examples and examples. It should however be borne in mindthat the present invention will not be limited to or by the followingexamples.

Referential Example 1 Synthesis of2′,4′-difluoro-2-(cyclopropylthio)acetophenone [Compound (4-1)]

To a solution of 2-chloro-2′,4′-difluoroacetophenone (2.8 g, 0.015 mol)in methanol (100 ml), a solution of cyclopropylmercaptane in ether, saidcyclopropylmercaptane having been obtained from cyclopropyl bromide (4.8g, 0.039 mol) by the method as described in J. Am. Chem. Soc., 114,3492(1992), was added, followed by the addition of potassium carbonate(2.5 g, 0.018 mol) under ice cooling. The resulting mixture was stirredat room temperature for 1.5 hours. After the completion of the reaction,the solvent was distilled off under reduced pressure. Water was added tothe residue, followed by extraction with ether. The extract was washedsuccessively with water and saturated saline and dried over magnesiumsulfate. The solvent was then distilled off under reduced pressure. Theresulting oil was distilled under reduced pressure (120° C., 2 mmHg),whereby 2′,4′-difluoro-2-(cyclopropylthio)acetophenone (2.3 g, yield:67%) was obtained as a colorless oil.

¹H-NMR(CDCl₃, δ): 0.41-0.96(4H,m), 1.72-1.98(1H,m), 3.85(2H,d,J=2 Hz),6.76-7.10(2H,m), 7.87-8.14(1H,m).

Referential Example 2 Synthesis of2-(cyclopropylthio)-4′-fluoroacetophenone [Compound (4-2)]

In a similar manner to Referential Example 1 except for the use of2-chloro-4′-fluoroacetophenone instead of2-chloro-2′,4′-difluoroacetophenone,2-(cyclopropylthio)-4′-fluoroacetophenone was obtained as a colorlessoil.

¹H-NMR(CDCl₃, δ): 0.48-1.05(4H,m), 1.86-2.03(1H,m), 3.86(2H,s),7.04-7.26(2H,m), 7.94-8.10(2H,m).

Referential Example 3 Synthesis of2-(cyclopropylthio)-4′-(trifluoromethyl)acetophenone [Compound (4-3)]

In a similar manner to Referential Example 1 except for the use of2-bromo-4′-(trifluoromethyl)acetophenone instead of2-chloro-2′,4′-difluoroacetophenone,2-(cyclopropylthio)-4′-(trifluoromethyl)acetophenone was obtained as acolorless oil.

¹H-NMR(CDCl₃, δ): 0.45-0.99(4H,m), 1.77-2.03(1H,m), 3.89(2H,s),7.73(2H,d,J=8 Hz), 8.09(2H,d,J=8 Hz).

Example 1 Synthesis of2-cyclopropylthio-2,2,2′,4′-tetrafluoroacetophenone [Compound (2-1)

To a solution of 2′,4′-difluoro-2-(cyclopropylthio)acetophenone (13.6 g,0.059 mol) in 1,1,2-trichloroethane (300 ml),N-fluoro-4-methylpyridinium-2-sulfonate (“MEC-02”, trade name; DaikinIndustries Ltd.) (29.6 g, 0.155 mol) was added in portions at aninternal temperature of 90° C., followed by stirring at an internaltemperature of 90 to 93° C. for 2 hours. After the completion of thereaction, the internal temperature was cooled to 50° C. or lower. Waterwas added to the reaction mixture, followed by extraction with1,1,2-trichloroethane. The extract was washed successively with waterand saturated saline and dried over magnesium sulfate. The solvent wasthen distilled off under reduced pressure. The resulting oil wassubjected to chromatography on a silica gel column and from thechloroform eluate fraction,2-cyclopropylthio-2,2,2′,4′-tetrafluoroacetophenone (5.6 g, yield: 36%)was obtained as a colorless oil.

¹H-NMR(CDCl₃, δ): 0.70-1.05(4H,m), 1.94-2.29(1H,m), 6.81-7.07(2H,m),7.85-8.11(1H,m)

Example 2 Synthesis of 2-cyclopropylthio-2,2,4′-trifluoroacetophenone[Compound (2-2)]

In a similar manner to Example 1 except for the use of2-(cyclopropylthio)-4′-fluoroacetophenone instead of2′,4′-difluoro-2-(cyclopropylthio)acetophenone,2-cyclopropylthio-2,2,4′-trifluoroacetophenone was obtained as acolorless oil.

¹H-NMR(CDCl₃, δ): 0.60-1.05(4H,m), 1.98-2.24(1H,m), 7.07-7.26(2H,m),8.10-8.26(2H,m)

Example 3 Synthesis of2-cyclopropylthio-2,2-difluoro-4′-(trifluoromethyl)acetophenone[Compound (2-3)]

In a similar manner to Example 1 except for the use of2-(cyclopropylthio)-4′-(trifluoromethyl)acetophenone instead of2′,4′-difluoro-2-(cyclopropylthio)acetophenone,2-cyclopropylthio-2,2-difluoro-4′-(trifluoromethyl)acetophenone wasobtained as a colorless oil.

¹H-NMR(CDCl₃, δ): 0.61-1.13(4H,m), 1.92-2.12(1H,m), 7.76(2H,d,J=8 Hz),8.24(2H,d,J=8 Hz).

Example 4 Synthesis of2-[(cyclopropylthio)(difluoro)methyl]-2-(2,4-difluorophenyl)oxirane[Compound (3-1)]

A suspension of 60% sodium hydride (1.0 g, 0.025 mol) in tetrahydrofuran(50 ml)—dimethylsulfoxide (70 ml) was heated to an external temperatureof 50° C., followed by the addition of trimethylsulfoxonium iodide (5.6g, 0.025 mol) in portions. After stirring at the same temperature forone hour, the reaction mixture was cooled to −20° C. and added dropwisewith a solution of 2-cyclopropylthio-2,2,2′,4′-tetrafluoroacetophenone(5.6 g, 0.021 mol) in tetrahydrofuran (20 ml). The resulting mixture wasstirred at room temperature for 2 hours. The reaction mixture was thenpoured into ice water, followed by extraction with ethyl acetate. Theextract was washed successively with water and saturated saline anddried over magnesium sulfate. The solvent was then distilled off underreduced pressure, whereby2-[(cyclopropylthio)(difluoro)methyl]-2-(2,4-difluorophenyl)oxirane (5.0g, yield: 86%) was obtained as a pale yellow oil.

¹H-NMR(CDCl₃, δ): 0.66-0.98(4H,m), 1.93-2.25(1H,m), 2.95-2.98(1H,m),3.48(1H,d,J=5 Hz), 6.71-6.99(2H,m), 7.40-7.65(1H,m).

Example 5 Synthesis of2-[(cyclopropylthio)(difluoro)methyl]-2-(4-fluorophenyl)oxirane[Compound (3-2)]

In a similar manner to Example 4 except for the use of2-cyclopropylthio-2,2,4′-trifluoroacetophenone instead of2-cyclopropylthio-2,2,2′,4′-tetrafluoroacetophenone,2-[(cyclopropylthio)(difluoro)methyl]-2-(4-fluorophenyl)oxirane wasobtained as a pale yellow oil.

¹H-NMR(CDCl₃, δ): 0.57-1.03(4H,m), 1.94-2.21(1H,m), 2.81-2.90(1H,m),3.46(1H,d,J=5 Hz), 6.91-7.15(2H,m), 7.44-7.60(2H,m).

Example 6 Synthesis of2-[(cyclopropylthio)(difluoro)methyl]-2-(4-trifluoromethyl)phenyloxirane[Compound (3-3)]

In a similar manner to Example 4 except for the use of2-cyclopropylthio-2,2-difluoro-4′-(trifluoromethyl)acetophenone insteadof 2-cyclopropylthio-2,2,2′,4′-tetrafluoroacetophenone,2-[(cyclopropylthio)(difluoro)methyl]-2-(4-trifluoromethylphenyl)oxiranewas obtained as a pale yellow oil.

¹H-NMR(CDCl₃, δ): 0.59-1.04(4H,m), 2.00-2.12(1H,m), 2.80-2.89(1H,m),3.50(1H,d,J=6 Hz), 7.65(4H,br.s).

Example 7 Synthesis of1-(cyclopropylthio)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)-2-propanol[Compound (1a-1)]

To a solution of2-[(cyclopropylthio)(difluoro)methyl]-2-(2,4-difluorophenyl)oxirane (5.0g, 0.017 mol) in DMSO (70 ml), 1,2,4-triazole (3.48 g, 0.05 mol) andpotassium carbonate (6.95 g, 0.05 mol) were added, followed by stirringat 55° C. for 1.5 hours. After the completion of the reaction, water wasadded to the reaction mixture. The resulting mixture was extracted withethyl acetate. The extract was washed successively with water andsaturated saline and dried over magnesium sulfate. The solvent was thendistilled off under reduced pressure. The residue so obtained wascrystallized from isopropyl ether—ethyl acetate, whereby1-(cyclopropylthio)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)-2-propanol(2.35 g, yield: 32%) was obtained as colorless crystals.

Melting point: 99 to 102° C.; IR(KBr) υ_(max)cm⁻¹: 3111, 1685, 1508,1148; MS(FAB): 348(M+H); ¹H-NMR(CDCl₃, δ): 0.58-1.06(4H,m),1.89-2.14(1H,m), 4.79(1H,d,J=14 Hz), 5.28(1H,d,J=14 Hz), 5.65(1H,s),6.60-6.95(2H,m), 7.58-7.85(1H,m), 7.81(1H,s), 8.08(1H,s).

Example 8 Synthesis of1-(cyclopropylthio)-1,1-difluoro-2-(4-fluorophenyl)-3-(1H-1,2,4-triazol-1-yl)-2-propanol[Compound (1a-2)]

In a similar manner to Example 7 except for the use of2-[(cyclopropylthio)(difluoro)methyl]-2-(4-fluorophenyl)oxirane insteadof 2-[(cyclopropylthio)(difluoro)methyl]-2-(2,4-difluorophenyl)oxirane,1-(cyclopropylthio)-1,1-difluoro-2-(4-fluorophenyl)-3-(1H-1,2,4-triazol-1-yl)-2-propanolwas obtained as colorless crystals.

Melting point: 101 to 102° C.; IR(KBr) υ_(max)cm⁻¹: 3143, 1607, 1511,1141; MS(FAB): 330(M+H); ¹H-NMR(CDCl₃, δ): 0.60-0.94(4H,m),1.88-2.10(1H,m), 4.68(1H,d,J=15 Hz), 4.90(1H,d,J=15 Hz), 5.26(1H,s),6.92-7.11(2H,m), 7.44-7.60(2H,m), 7.85(1H,s), 7.91(1H,s).

Example 9 Synthesis of1-(cyclopropylthio)-1,1-difluoro-2-(4-trifluoromethylphenyl)-3-(1H-1,2,4-triazol-1-yl)-2-propanol[Compound (1a-3)]

In a similar manner to Example 7 except for the use of2-[(cyclopropylthio)(difluoro)methyl]-2-(4-trifluoromethylphenyl)oxiraneinstead of2-[(cyclopropylthio)(difluoro)methyl]-2-(2,4-difluorophenyl)oxirane,1-(cyclopropylthio)-1,1-difluoro-2-(4-trifluoromethylphenyl)-3-(1H-1,2,4-triazol-1-yl)-2-propanolwas obtained as colorless crystals.

Melting point: 114 to 115° C.; IR(KBr) υ_(max)cm⁻¹: 3140, 1621, 1514,1139; MS(FAB): 380(M+H); ¹H-NMR(CDCl₃, δ): 0.55-1.03(4H,m),1.85-2.18(1H,m), 4.68(1H,d,J=14 Hz), 4.90(1H,d,J=14 Hz), 5.70(1H,s),7.46-7.76(4H,m), 7.81(1H,s), 7.94(1H,s).

Example 10 Synthesis of1-[3-(cyclopropylthio)-2-(2,4-difluorophenyl)-3,3-difluoro-2-methoxypropyl]-1H-1,2,4-triazole[Compound (1a-4)]

To a solution of 60% sodium hydride (75 mg, 1.87 mmol) inN,N-dimethylformamide (50 ml),1-(cyclopropylthio)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)-2-propanol(0.50 g, 1.44 mmol) was added dropwise under ice cooling, followed bystirring at room temperature for 30 minutes. Methyl iodide (270 mg, 1.87mmol) was then added dropwise to the reaction mixture under ice coolingand the resulting mixture was stirred at room temperature for 1 hour.Water was added to the reaction mixture, followed by extraction withether. The ether solution was washed with water and dried over sodiumsulfate. The solvent was then distilled off under reduced pressure. Theresidue was subjected to a silica gel column and from the chloroformeluate fraction,1-[3-(cyclopropylthio)-2-(2,4-difluorophenyl)-3,3-difluoro-2-methoxypropyl]-1H-1,2,4-triazole(0.31 g, yield: 60%) was obtained as a colorless oil.

MS (FAB): 362(M+H); ¹H-NMR(CDCl₃, δ): 0.54-0.98(4H,m), 1.85-2.10(1H,m),3.70(3H,fine t,J=2 Hz), 5.09(2H,t,J=15 Hz), 6.65-6.94(2H,m),7.46-7.66(1H,m), 7.78(1H,s), 7.98(1H,s).

Example 11 Synthesis of1-[2-(benzyloxy)-3-(cyclopropylthio)-2-(2,4-difluorophenyl)-3,3-difluoropropyl]-1H-1,2,4-triazole[Compound (1a-5)]

In a similar manner to Example 10 except for the use of benzyl chlorideinstead of methyl iodide,1-[2-(benzyloxy)-3-(cyclopropylthio)-2-(2,4-difluorophenyl)-3,3-difluoropropyl]-1H-1,2,4-triazolewas obtained as a colorless oil.

MS(FAB): 438(M+H); ¹H-NMR(CDCl₃, δ): 0.56-0.99(4H,m), 1.93-2.18(1H,m),4.85(1H,d,J=14 Hz), 5.13(1H,d,J=14 Hz), 5.21(1H,br.s), 6.69-6.90(2H,m),7.38(5H,s), 7.46-7.64(1H,m), 7.77(1H,s), 7.93(1H,s).

Example 12 Synthesis of1-(cyclopropylsulfonyl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)-2-propanol[Compound (1c-1)]

To a solution of1-(cyclopropylthio)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)-2-propanol(2.3 g, 6.63 mmol) in dichloromethane (200 ml), 85% m-chloroperbenzoicacid (3.6 g, 14.58 mmol) was added at room temperature, followed bystirring at room temperature for 12 hours. After the completion of thereaction, a saturated aqueous solution of sodium thiosulfate and asaturated aqueous solution of sodium bicarbonate were added and theresulting mixture was stirred. The dichloromethane solution wasseparated and after washing with water, dried over magnesium sulfate.The solvent was then distilled off under reduced pressure. The residueso obtained was crystallized from isopropyl ether—ethyl acetate, whereby1-(cyclopropylsulfonyl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)-2-propanol(1.9 g, yield: 76%) was obtained as colorless crystals.

Melting point: 155 to 156° C.; IR(KBr) υ_(max)cm⁻¹: 3111, 1613, 1504,1346; MS(FAB): 380(M+H); ¹H-NMR(CDCl₃, δ): 1.12-1.45(4H,m),2.67-2.73(1H,m), 5.19(1H,d,J=14 Hz), 5.33(1H,d,J=14 Hz), 5.92(1H,s),6.65-6.93(2H,m), 7.67-7.73(1H,m), 7.79(1H,s), 8.07(1H,s).

Example 13 Synthesis of1-(cyclopropylsulfonyl)-2-(4-fluorophenyl)-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)-2-propanol[Compound (1c-2)]

In a similar manner to Example 12 except for the use of1-(cyclopropylthio)-2-(4-fluorophenyl)-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)-2-propanolinstead of1-(cyclopropylthio)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)-2-propanol,1-(cyclopropylsulfonyl)-2-(4-fluorophenyl)-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)-2-propanolwas obtained as colorless crystals.

Melting point: 197 to 199° C.; IR(KBr) υ_(max)cm⁻¹: 3088, 1604, 1508,1333; MS(FAB): 362(M+H); ¹H-NMR(CDCl₃, δ): 1.10-1.18(4H,m),2.77-2.81(1H,m), 4.99(1H,d,J=15 Hz), 5.14(1H,d,J=15 Hz),7.09-7.14(2H,m), 7.54-7.58(2H,m), 7.72(1H,s), 8.21(1H,s).

Example 14 Synthesis of1-(cyclopropylsulfonyl)-1,1-difluoro-2-(4-trifluoromethylphenyl)-3-(1H-1,2,4-triazol-1-yl)-2-propanol[Compound (1c-3)]

In a similar manner to Example 12 except for the use of1-(cyclopropylthio)-1,1-difluoro-2-(4-trifluoromethylphenyl)-3-(1H-1,2,4-triazol-1-yl)-2-propanolinstead of1-(cyclopropylthio)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)-2-propanol,1-(cyclopropylsulfonyl)-1,1-difluoro-2-(4-trifluoromethylphenyl)-3-(1H-1,2,4-triazol-1-yl)-2-propanolwas obtained as colorless crystals.

Melting point: 194 to 195° C.; IR(KBr) υ_(max)cm⁻¹: 3080, 1620, 1514,1324; MS(FAB): 412(M+H); ¹H-NMR(CDCl₃, δ): 1.12-1.21(4H,m),5.03(1H,d,J=15 Hz), 5.20(1H,d,J=15 Hz), 5.56(1H,s), 7.66(2H,d,J=8 Hz),7.70(1H,s), 7.75(2H,d,J=8 Hz), 8.26(1H,s).

Example 15 Synthesis of1-[3-(cyclopropylsulfonyl)-2-(2,4-difluorophenyl)-3,3-difluoro-2-methoxypropyl]-1H-1,2,4-triazole[Compound (1c-4)]

In a similar manner to Example 12 except for the use of1-[3-(cyclopropylthio)-2-(2,4-difluorophenyl)-3,3-difluoro-2-methoxypropyl]-1H-1,2,4-triazoleinstead of1-(cyclopropylthio)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)-2-propanol,1-[3-(cyclopropylsulfonyl)-2-(2,4-difluorophenyl)-3,3-difluoro-2-methoxypropyl]-1H-1,2,4-triazolewas obtained as a colorless oil.

MS(FAB): 394(M+H); ¹H-NMR(CDCl₃, δ): 1.11-1.47(4H,m), 2.46-2.62(1H,m),3.75(3H,s), 5.11(1H,d,J=15 Hz), 5.36(1H,d,J=15 Hz), 6.68-6.98(2H,m),7.45-7.72(1H,m), 7.79(1H,s), 8.08(1H,s).

Example 16 Synthesis of1-[2-(benzyloxy)-3-(cyclopropylsulfonyl)-2-(2,4-difluorophenyl)-3,3-difluoropropyl]-1H-1,2,4-triazole[Compound (1c-5)]

In a similar manner to Example 12 except for the use of1-[2-(benzyloxy)-3-(cyclopropylthio)-2-(2,4-difluorophenyl)-3,3-difluoropropyl]-1H-1,2,4-triazoleinstead of1-(cyclopropylthio)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)-2-propanol,1-[2-(benzyloxy)-3-(cyclopropylsulfonyl)-2-(2,4-difluorophenyl)-3,3-difluoropropyl]-1H-1,2,4-triazolewas obtained as colorless crystals.

Melting point: 124 to 125° C.; IR(KBr) υ_(max)cm⁻¹: 1616, 1499, 1347;(FAB): 470(M+H); ¹H-NMR(CDCl₃, δ): 1.10-1.15(2H,m), 1.33-1.37(2H,m),2.50-2.54(1H,m), 5.02(1H,d,J=10 Hz), 5.11(1H,d,J=10 Hz), 5.31(1H,d,J=15Hz), 5.45(1H,d,J=15 Hz), 6.80-6.87(2H,m), 7.31-7.46(5H,m),7.58-7.64(1H,m), 7.79(1H,s), 8.02(1H,s).

Example 17 Optical resolution of1-(cyclopropylsulfonyl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)-2-propanol

(±)-1-(Cyclopropylsulfonyl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)-2-propanol(30 mg) was subjected to CHIRALCEL OD (trade name; product of DaicelChemical Industries, Ltd.), that is, a column for the separation of anoptically active substance. From the eluate fraction of a 4:1hexane—isopropyl alcohol mixture, 14 mg (optical purity: 100% e.e.) ofthe (+) form as colorless crystals and 13 mg (optical purity: 100% e.e.)of the (−) form as colorless crystals were obtained in the order ofelution.

(1)(+)-1-(Cyclopropylsulfonyl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)-2-propanol

[α]_(D) ^(21.7) +22.5° (C=0.1, acetone); Melting point: 130 to 132° C.;IR(KBr) υ_(max)cm⁻¹: 3111, 1613, 1504, 1346; MS(FAB): 380(M+H);¹H-NMR(CDCl₃, δ): 1.12-1.45(4H,m), 2.67-2.73(1H,m), 5.19(1H,d,J=14 Hz),5.33(1H,d,J=14 Hz), 5.92(1H,s), 6.65-6.93(2H,m), 7.67-7.73(1H,m),7.79(1H,s), 8.07(1H,s).

(2)(−)-1-(Cyclopropylsulfonyl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)-2-propanol

[α]_(D) ^(21.7) −24.5° (C=0.1, acetone); Melting point: 130 to 132° C.;IR(KBr) υ_(max)cm⁻¹: 3111, 1613, 1504, 1346; MS(FAB): 380(M+H);¹H-NMR(CDCl₃, δ): 1.12-1.45(4H,m), 2.67-2.73(1H,m), 5.19(1H,d,J=14 Hz),5.33(1H,d,J=14 Hz), 5.92(1H,s), 6.65-6.93(2H,m), 7.67-7.73(1H,m),7.79(1H,s), 8.07(1H,s).

Example 18 Optical resolution of1-(cyclopropylsulfonyl)-2-(4-fluorophenyl)-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)-2-propanol

(±)-1-(Cyclopropylsulfonyl)-2-(4-difluorophenyl)-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)-2-propanol(30 mg) was subjected to CHIRALCEL OD (trade name; product of DaicelChemical Industries, Ltd.), that is, a column for the separation of anoptically active substance. From the eluate fraction of a 2:1hexane—isopropyl alcohol mixture, 10 mg (optical purity: 100% e.e.) ofthe (+) form as colorless crystals and 10 mg (optical purity: 100% e.e.)of the (−) form as colorless crystals were obtained in the order ofelution.

(1)(+)-1-(Cyclopropylsulfonyl)-2-(4-fluorophenyl)-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)-2-propanol

[α]_(D) ^(21.7) +22.5° (C=0.1, acetone); Melting point: 144 to 145° C.;IR(KBr) υ_(max)cm⁻¹: 3122, 1605, 1514, 1332; MS(FAB): 362(M+H);¹H-NMR(CDCl₃, δ): 1.10-1.18(4H,m), 2.77-2.81(1H,m), 4.99(1H,d,J=15 Hz),5.14(1H,d,J=15 Hz), 7.09-7.14(2H,m), 7.54-7.58(2H,m), 7.72(1H,s),8.21(1H,s).

(2)(−)-1-(Cyclopropylsulfonyl)-2-(4-fluorophenyl)-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)-2-propanol

[α]_(D) ^(21.7) −23.5° (C=0.1, acetone); Melting point: 145 to 146° C.;IR(KBr) υ_(max)cm⁻¹: 3122, 1605, 1514, 1332; MS(FAB): 362(M+H);¹H-NMR(CDCl₃, δ): 1.10-1.18(4H,m), 2.77-2.81(1H,m), 4.99(1H,d,J=15 Hz),5.14(1H,d,J=15 Hz), 7.09-7.14(2H,m), 7.54-7.58(2H,m), 7.72(1H,s),8.21(1H,s).

Test 1: Action against Candida albicans (in vitro)

To each well of a 96-well microtiter plate, 75 μl of a dilute medicamentsolution adjusted with a 10% fetal-bovine-serum added MEM medium(containing glutamine and a carbonate) were poured, followed by theaddition of 75 μl of 4×10⁴ cells/ml of C. albicans ATCC 44859 suspendedin the same medium. The resulting mixture was incubated at 37° C. for 24hours in a CO₂ gas incubator. After incubation, a morphological changeof C. albicans was observed under an inverted microscope. The minimummedicament concentration permitting the apparent suppression of mycerialtype growth compared with that of a medicament-free control wasdesignated as a terminal point (ng/ml). Incidentally, as a medicamentfor comparison, Fluconazole and known compound A [(−)-compound (1c-1) inJapanese Patent Application Laid-Open No. HEI 9-227531] were employed.The results are shown in Table 1.

Test 2: Action against Aspergillus fumigatus (in vitro)

To each well of a 96-well microtiter plate, 100 μl of a dilutemedicament solution adjusted with 0.165M MOPS-containing RPMI 1640medium (containing glutamine and phenol red, carbonate free; pH 7) werepoured, followed by the addition of 100 μl of 6.0×10⁴ conidia/ml of anA. fumigatus IFM 40808 spore suspension in the above medium containing20% almar Blue. They were incubated at 35° C. for 48 hours. Judgment wasmade visually and the minimum medicament concentration which did notcause a change of color of the medium into red (at which the color ofthe medium was still maintained blue) was designated as an MIC value(μg/ml). Incidentally, as a medicament for comparison, Fluconazole andknown compound A ((−)-compound (1c-1) in Japanese Patent ApplicationLaid-Open No. HEI 9-227531) were employed. The results are shown inTable 1.

TABLE 1 Terminal point (ng/ml) MIC (μg/ml) Test compound C. albicans A.fumigatus Example 7 7.8 2 Example 8 15.6 8 Example 10 31.3 32 Example 1231.3 8 Example 17(2) 15.6 2 Fluconazole 250 >128 Known compound A 62.516

Test 3: Action against Candida albicans (in vivo)

After 4-week-old, male, ICR (CRJ: CD-1) mice were fasted for 6 hours, C.albicans IFM 40009 was inoculated to the tail vein of each of the miceto give an amount of 3.0×10⁶ cells/mouse, whereby infection was caused.A control group consisted of 11 mice, while a medicament-administeredgroup consisted of 5 mice. The medicament dissolved in 20% polyethyleneglycol was orally administered 1 hour after the inoculation of thefungus and from 24 hours after the inoculation, it was administered oncea day for 4 straight days, each in an amount of 1.25 mg/kg. The survivalcondition on Day 14 after the infection was compared. In addition, thesurvival days of the control group and the medicament-administered groupwere detected by the Kaplan-Meier method (Cox mantel test).Incidentally, Fluconazole was employed as a medicament for comparison.The results are shown in Table 2.

TABLE 2 Surviving mice on Day 14 number of surviving Average Sur-mice/total number Test compound vival days in group Example 12 14.00***4/5 Example 15 13.4*** 4/5 Fluconazole 11.0*** 1/5 Control 4.5 0/11(relative to control: *** p < 0.001)

Example 19: Tablets

Compound of Example 17(2)  50 mg Crystalline cellulose  50 mg Lactose 50 mg Hydroxypropyl cellulose  18 mg Magnesium stearate  2 mg Total 170mg

In a conventional manner, tablets having the above-described compositionwere prepared. The tablets can be formed as sugar coated tablets or filmcoated tablets as needed.

Example 20: Capsules

Compound of Example 17(2)  50 mg Light silicic anhydride  25 mg Lactose100 mg Starch  50 mg Talc  25 mg Total 250 mg

The above ingredients were filled in No. 1 capsules, whereby capsuleswere obtained.

Example 21: Granules

Compound of Example 17(2)  50 mg Lactose  600 mg Corn starch  200 mgCarboxymethyl cellulose sodium  20 mg Hydroxypropyl cellulose  130 mgTotal 1000 mg

In a conventional manner, granules having the above-describedcomposition were prepared.

Example 22: Powders

Compound of Example 17(2)  50 mg Light silicic anhydride  20 mgPrecipitated calcium carbonate  10 mg Lactose 250 mg Starch  70 mg Total400 mg

In a conventional manner, powders having the above-described compositionwere prepared.

Example 23: Injection

Compound of Example 17(2)  5 mg Hydrogenated castor oil 85 mg Propyleneglycol 60 mg Glucose 50 mg Distilled water for injection q.s. Total  1ml

In a conventional manner, an injection having the above-describedcomposition was prepared.

Example 24: Intravenous Drip Infusion

Compound of Example 17(2)  50 mg Hydrogenated castor oil  5 g Propyleneglycol  10 mg Glucose  14.5 mg Distilled water for injection q.s. Total100 ml

An intravenous drip infusion having the above-described composition wasprepared in a conventional manner.

What is claimed is:
 1. An oxirane derivative represented by thefollowing formula (3):

wherein X¹ and X² are the same or different and each independentlyrepresents a hydrogen atom, a halogen atom or a halogenoalkyl group of 1to 6 carbons.